Abstract We propose to evaluate risk factors for epithelial ovarian cancer using questionnaire data, biological samples, and paraffin-embedded ovarian tumor tissue from women in the Nurses' Health Study (NHS), NHSII, and the New England Case-Control Study (tumor tissue aims only). Although several hypotheses regarding ovarian cancer etiology have been proffered, few currently confirmed risk factors are easily modifiable. Thus, a major focus of the current proposal is on modifiable or treatable factors within two key, yet underexplored, pathways in ovarian cancer etiology: lipids and inflammation. For the lipid pathway, we will examine plasma total cholesterol, HDL, and LDL as these markers can be altered by medication or lifestyle changes, as well as several other promising lipid classes, lysophosphatidylcholines and sphingomyelins, which have been suggested as early detection markers and also be important etiologically. These will be measured on a validated, semi-targeted metabolomics platform; this also will allow us to conduct a comprehensive discovery- based analysis of other small molecule metabolites that may be important in ovarian carcinogenesis. The inflammation aims will build on work from the current P01 and cross-project collaboration with Project 2 (colorectal cancer), taking an innovative approach that considers multiple facets of the inflammatory milieu, including lifestyle factors (pro-inflammatory diet, sedentary behavior, strength training), analgesic related factors (premenopausal NSAID use, urinary prostaglandins), and chlamydia infection status. Importantly, we will explore potential underlying biologic mechanisms of action by evaluating risk factor associations by tumor aggressiveness, the amount of tumor-associated macrophage infiltration, and global tumor gene expression to identify transcriptional alterations in tumors of patients with varying inflammatory exposures. We propose to provide the first detailed evaluation of modifiable factors after diagnosis, including physical activity, smoking, NSAIDs, and a pro-inflammatory diet, and survival in stage I/II patients; no evidence-based recommendations currently are available. Major strengths of this study include the large sample size, up to 40 years of questionnaire data (collected pre- and post-diagnosis in cases), archived plasma and urine samples, detailed medical record data as well as tumor tissue from ovarian cancer cases, allowing careful examination of timing of exposure in relation to disease risk and survival. Cumulatively, these rich resources will allow us to examine novel modifiable or treatable risk factors from prevention to early detection to survival. Moreover, we will benefit from integration and synergy with similar research across cancers in this Program Project as well as investigators from multiple fields and institutions, including a pre-eminent clinical cancer center - providing added value by enabling cross-fertilization in science and bioinformatics, eventually yielding new insignts into underlying or common pathways in cancer development, and the possibility of rapid clinical translation.